Pruning nature: Biodiversity-derived discovery of novel sodium channel blocking conotoxins from Conus bullatus.
Described herein is a general approach to identify novel compounds using the biodiversity of a megadiverse group of animals; specifically, the phylogenetic lineage of the venomous gastropods that belong to the genus Conus ("cone snails"). Cone snail biodiversity was exploited to identify three new mu-conotoxins, BuIIIA, BuIIIB and BuIIIC, encoded by the fish-hunting species Conus bullatus. BuIIIA, BuIIIB and BuIIIC are strikingly divergent in their amino acid composition compared to previous mu-conotoxins known to target the voltage-gated Na channel skeletal muscle subtype Na(v)1.4. Our preliminary results indicate that BuIIIB and BuIIIC are potent inhibitors of Na(v)1.4 (average block approximately 96%, at a 1muM concentration of peptide), displaying a very slow off-rate not seen in previously characterized mu-conotoxins that block Na(v)1.4. In addition, the three new C. bullatus mu-conopeptides help to define a new branch of the M-superfamily of conotoxins, namely M-5. The exogene strategy used to discover these Na channel-inhibiting peptides was based on both understanding the phylogeny of Conus, as well as the molecular genetics of venom mu-conotoxin peptides previously shown to generally target voltage-gated Na channels. The discovery of BuIIIA, BuIIIB and BuIIIC Na channel blockers expands the diversity of ligands useful in determining the structure-activity relationship of voltage-gated sodium channels.
Holford
Mandë
M
Department of Biology, University of Utah, 257 S. 1400 E. Rm. 114, Salt Lake City, UT 84112, USA. holford@biology.utah.edu
Zhang
Min-Min
MM
Gowd
K Hanumae
KH
Azam
Layla
L
Green
Brad R
BR
Watkins
Maren
M
Ownby
John-Paul
JP
Yoshikami
Doju
D
Bulaj
Grzegorz
G
Olivera
Baldomero M
BM
D051046:Amino-Acid N-Acetyltransferase; D000818:Animals; D001483:Base Sequence; D044822:Biodiversity; D003001:Cloning, Molecular; D020916:Conotoxins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D052078:Conus Snail / Q000235:genetics* / Q000502:physiology*; D018076:DNA, Complementary; D008978:Mollusk Venoms / Q000737:chemistry; D009865:Oocytes; D010802:Phylogeny; D026941:Sodium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism; D014981:Xenopus
D020916:Conotoxins; D018076:DNA, Complementary; D008978:Mollusk Venoms; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D051046:Amino-Acid N-Acetyltransferase